Hepatitis C virus (HCV) is the leading cause of chronic hepatitis, which can progress to liver fibrosis leading to cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma), making it the leading cause of liver transplantations. Current anti-HCV therapy, based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin, suffers from limited efficacy, significant side effects, and is poorly tolerated in many patients. This prompted the search for more effective, convenient and better-tolerated therapy.
Replication of the genome of HCV is mediated by a number of enzymes, amongst which is HCV NS3 serine protease and its associated cofactor, NS4A. Various agents that inhibit this enzyme have been described. WO 05/073195 discloses linear and macrocyclic NS3 serine protease inhibitors with a central substituted proline moiety and WO 05/073216 with a central cyclopentyl moiety. Amongst these, the macrocyclic derivatives are attractive by their pronounced activity against HCV and attractive pharmacokinetic profile.
WO 2007/014926 describes macrocyclic cyclopentyl and proline derivatives including the compound of formula (I), with the structure represented hereafter. The compound of formula (I) is a very effective inhibitor of the HCV serine protease and is particularly attractive due to its favorable pharmacokinetical profile. Because of its properties this compound has been selected as a potential candidate for development as an anti-HCV drug. Consequently there is a need for producing larger quantities of this active ingredient based on processes that provide the product in high yield and with a high degree of purity. WO 2008/092955 describes processes and intermediates to prepare the compound of formula (I).

The compound of formula (I) can be prepared starting from an intermediate (VI), wherein the ester function is hydrolysed, yielding carboxylic acid (V), which in turn is coupled in an amide forming reaction with the cyclopropyl amino acid (Va). The resulting intermediate (IV) is cyclized by an olefin metathesis reaction in the presence of a suitable metal catalyst such as e.g. an ylidene Ru-based catalyst. The resulting macrocyclic ester (III) is then hydrolyzed to macrocyclic acid (IV). The latter is coupled with a sulfonylamide (V) in an amide forming reaction to yield the end product (I). These reactions are outlined in the reaction scheme herebelow. In this and the following reaction schemes or representations of individual compounds, R is C1-4alkyl, in particular R is C1-3alkyl, more in particular R is C1-2alkyl, or in one embodiment R is ethyl. R1 is C1-4alkyl, in particular R1 is C1-3alkyl, more in particular R1 is C1-2alkyl, or R1 is methyl; or R1 is ethyl.

Intermediate (VI) in turn can be prepared using procedures described in WO 2008/092955, in particular starting from a hydroxycyclopentyl bis-ester of formula (Xa), by either    (a) reacting the hydroxycyclopentyl bis-ester of formula (Xa) with a thiazolyl substituted quinolinol (VII) in an ether forming reaction, thus obtaining a quinolinyloxycyclopentyl bis-ester of formula (XII), wherein the benzyl ester group that is in cis position vis-à-vis the ether group in the quinolinyloxy-cyclopentyl bis-ester of formula (XII) is selectively cleaved to a mono carboxylic acid (XI), which in turn is coupled with an alkenylamine in an amide forming reaction, thus obtaining the desired end product of formula (VI); or    (b) selectively converting the hydroxycyclopentyl bis-ester of formula (Xa) to the mono carboxylic acid (IX), which in turn is coupled with an alkenylamine in an amide forming reaction to obtain hydroxycyclopentylamide (VIII), which in turn is reacted with a thiazolyl substituted quinolinol (VII), thus obtaining the desired end product of formula (VI); as outlined in the following reaction scheme:

Each R1 in the processes represented in the above scheme is as specified above and preferably R1 is methyl. Bn represents benzyl.
The presence of various chiral centers in the compound of formula (I) and its predecessors poses particular challenges in that chiral purity is essential to have a product that is acceptable for therapeutic use. The intermediate (VI) has three chiral centers and getting the correct stereochemistry for all three centers is an important challenge for any synthesis processes aimed at preparing this compound. Hence the processes for preparing (VI) should result in products of acceptable chiral purity without use of cumbersome purification procedures with the loss of substantial amounts of undesired stereoisomeric forms.
WO 2008/092955 describes a synthesis procedure for intermediate (Xa) starting from 4-oxo-cyclopentyl-1,2-bis-carboxylic acid (XVII) by reducing the keto function to an alcohol, thus obtaining 4-hydroxy-cyclopentyl-1,2-bis-carboxylic acid (XVI), which in turn is cyclized to the bicyclic lactone (XV), wherein the carboxylic acid group in the bicyclic lactone (XV) is esterified with benzyl alcohol thus obtaining the lactone benzyl ester (XIV). The lactone in the latter is opened by a transesterification reaction in the presence of a C1-4alkanol, thus yielding the hydroxycyclopentyl bis-ester of formula (X), which in turn is resolved in enantiomers (Xa) and (Xb); as outlined in the following reaction scheme:

Each R1 in the processes represented in the above scheme is as specified above and preferably R1 is methyl.
A disadvantage of the above process is that it involves a resolution of the enantiomers of (X) by chiral column chromatography, a cumbersome procedure that is difficult to run at large scale production.
Honda et al., Tetrahedron Letters, vol. 22, no. 28, pp 2679-2682, 1981, describes the synthesis of (±)-brefeldin A using the following starting materials:

The synthesis of Honda et al. starts from dl-trans-4-oxocyclopentane-1,2-dicarboxylic acid 2, which was esterified to the corresponding methyl ester 3, and reduced with Raney-Ni to the alcohol 4. Partial hydrolysis of 4 to the monocarboxylic acid and benzylation with benzyl bromide gave predominantly diastereoisomer 5, namely the diastereoisomer wherein the hydroxy and benzyl ester groups are in cis position. The latter ester 5 in Honda et al. and compound (X) are both racemates, but are diastereoisomers of each other, more precisely epimers on the carbon no. 4 bearing the hydroxy group. Compound (Xa) is one of the two enantiomers obtained by separation from the racemic compound (X). The other enantiomer is compound (Xb).
WO 2005/073195 describes the synthesis of enantiomercally pure bicyclic lactone (8b) starting from an enantiomer of 3,4-bis(methoxycarbonyl)cyclopentanone. The latter was prepared as described by Rosenquist et al. in Acta Chemica Scandinavica 46 (1992) 1127-1129. The trans (3R,4R)-3,4-bis(methoxycarbonyl)cyclopentanone isomer was converted to the bicyclic lactone (8b):

WO 2005/073195 additionally describes further modification of lactone (8b) to the t.Bu ester, opening of the lactone and coupling with appropriately protected amino acids, e.g. with (1R,2S)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester, which in the latter instance yields:

The build-up of the compounds of formula (I) necessarily involves introducing the thiazolyl substituted quinoline moiety on the cyclopentyl ring via an ether linkage. The Mitsunobu reaction offers an attractive reaction route for preparing aromatic alkylethers in which an alkyl ether is activated and reacted with a phenol. In addition, Mitsunobu reactions are in general more efficient than the O-arylation reactions, which require additional synthesis steps. In this mild reaction the stereochemistry of the alkyl part is inverted. The reaction gives rise to side products, such as R′OOC—NH—NH—COOR′, wherein R′ is C1-4alkyl and in particular ethyl or isopropyl, other nitrogen-containing compounds, and triphenylphosphine oxide, which need to be separated from the desired end product.
The processes of the present invention are advantageous in that they are suitable for large scale production. Cumbersome purification steps, in particular by chromatography, are avoided. Essential in the synthesis of the compound of formula (I) is the built-up of the cyclopentyl moiety with the right stereochemistry at its three chiral centers.
One of the aspects of this invention concerns processes for preparing the intermediates (VIII) in high yield and purity, especially in terms of chiral purity, that are fit for large scale industrial application.
The present invention is aimed at providing procedures to prepare cyclopentyl intermediates with the right stereochemistry, in high yield and purity. In particular the present invention concerns the preparation of the intermediates

which find use in the procedures to prepare the compound of formula (I).